Regeneration medical treatment is drawing attention as the regeneration therapy at the time of disorders of tissues and cells such as blood vessel, liver, kidney, lung, pancreas, bone, skeletal muscle cell, myocardial cell, peripheral and central nerve cells and the like. The self repair system includes a system which is attained by the cell division of mature cells (simple duplication system) like the regeneration of many parenchymal organs such as liver and kidney and a system mediated by the proliferation and differentiation induction of stem cells (precursor cells) (stem cell system) like the regeneration of hematopoietic cells. Presently, it is said that these two systems are present in the regeneration of many tissues and organs. For example, it is said that these two systems are present also in the angiogenesis (regeneration), and there are an angiogenesis system based on the growth of neighboring vascular endothelial cells, vascular smooth muscle cells and the like, effected by the release of various endogenous repair factors (e.g., vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), various fibroblast growth factors (a/b FGF), transformation growth factor-β(TGF-β), platelet derived growth factor (PDGF), angiopoietin, hypoxia inducing factor (HIF), insulin-like growth factor (IGF), bone morphogenetic protein (BMP), connective tissue growth factor (CTGF), epidermal growth factor (EGF), etc., growth factors of their families, and the like) from (vascular) endothelial cells, (vascular) smooth muscle cells, fibroblasts, synovial cells, epithelial cells, platelets, monocytes, lymphocytes, macrophages and the like of the injured (neighboring) region, and a vasculogenesis system in which blood vessel is formed by the differentiation induction of vascular endothelial stem cells from bone marrow cells of a matured individual, effected by the release of various inflammatory cytokines (e.g., IL-1, IL-4, IL-8, TNFα, IFNα/γ, G-CSF, GM-CSF, NO (nitric monoxide), etc.), and various endogenous repair factors.
Regarding the presence of stem cells (precursor cells), they are present not only in blood vessels but also in many tissues such as hepatocyte, pancreatic (β) cell, myocardial cell, kidney, lung, bone, joint, nerve, fat, skin and the like, and are proliferated and differentiation-induced by various endogenous repair factors, various inflammatory cytokines and the like.
When production of these endogenous repair factors is accelerated, formation of collateral circulation passage is accelerated by the effect of angiogenesis on the ischemic region. Also, it is known that prevention and treatment (repairing regeneration) of various organ disorders are accelerated by the differentiation induction action from various tissue stem cells. For example, it is known that HGF has a cell growth acceleration action, a morphogenesis inducing action, a differentiation inducing action, a wandering acceleration action, anti-apoptosis action and the like (e.g., see Biochem. Biophys. Res. Commun., 239, 639-644 (1997), etc.). It is known that these endogenous repair factor production accelerations are effective for the prevention and/or treatment of, for example, liver diseases (e.g., fluminant hepatitis, acute hepatitis, hepatic cirrhosis, fatty liver, liver transplantation, etc.), kidney diseases (e.g., acute renal insufficiency, chronic renal insufficiency, etc.), lung diseases (e.g., acute pneumonia, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, etc.), pancreas diseases (e.g., diabetes mellitus, chronic pancreatitis, etc.), bone diseases (e.g., osteoarthritis, articular rheumatism, osteoporosis, bone fracture, periosteum injury, etc.), digestive organ diseases (e.g., gastric ulcer, duodenal ulcer, ulcerative colitis, Crohn disease, etc.), nerve degeneration diseases (e.g., stroke, Parkinson disease, Alzheimer disease, spinal canal stenosis, cerebrovascular accidents, moyamoya disease, etc.), diabetic complications (e.g., nerve disorder, skin ulcer, nephropathy, retinal disease, etc.), vascular endothelial cell diseases (e.g., restenosis after PTCA (percutaneous transluminal coronary angioplasty), arteriosclerosis, etc.), heart diseases (e.g., supraventricular tachyarrhythmia, congestive heart failure, coronary artery disease, sudden cardiomyopathy, dilated cardiomyopathy, etc.), dental diseases (e.g., periodontal disease, tooth extraction wound, oral wound, periodontal tissue disease, etc.), decubitus, glaucoma, alopecia and the like.
The regeneration therapy mediated by endogenous repair factors is drawing attention as an angiogenesis (regeneration) therapy and a tissue generation therapy at the time of the diseases of organs and tissues such as liver, pancreas, kidney, heart, central/peripheral nerves, blood vessel, tooth, eye, periosteum, bone and the like. This is drawing attention particularly as a regeneration therapy of serious ischemic organ diseases having no therapeutic methods, and several methods are examined on arteriosclerosis obliterans (hereinafter referred to as “ASO”), Buerger disease, Raynaud disease, cardiovascular diseases (e.g., myocardial infarction, angina pectoris, etc.), diabetic neuropathy, spinal canal stenosis, ischemic brain disease (e.g., cerebrovascular accidents, cerebral infarction, etc.), pulmonary hypertension, bone fracture, or Alzheimer disease and the like.
For example, patients of obstructive peripheral blood vessel diseases typified by ASO and Buerger disease show intermittent claudication, pain during resting and ulcer and necrosis of the legs, and finally it becomes unavoidable to undergo amputation of the legs. However, at present, there is no therapeutic method effective for these serious ASO patients. Since intravenous injection of PGE 1 and a vasodilator or platelet agglutination inhibitor as an oral agent of cilostazol do not show their effects on serious ASO patients, an intravascular treatment (balloon dilation or Stent insertion) and revascularization cannot be carried out. Recently, a gene therapy in which a VEGF gene plasmid and an HGF gene plasmid are directly administered by intramuscular injection into skeletal muscles of ischemic regions of the legs of these patients (cf. Circulation, 97, 1114-1123 (1998) and Gene Therapy, 8, 181-189 (2001)) has been clinically applied, and its effect is drawing attention. In addition, slow release preparations of a growth factor protein (e.g., a gelatin inclusion sheet) have also been subjected to basal examinations (Circulation, 106, Supple 2, II 350 (2002)).
On the other hand, an angiogenesis therapy in which vascular endothelial stem cells separated from bone marrow or peripheral blood of a patient are directly administered into the ischemic region of a leg by intramuscular injection is drawing attention and is carried out at several university hospitals which is also drawing attention (cf. THE LANCET, 360, 427-435 (1002)).
Introduction of these genes and stem cells directly into ischemic regions using a vascular catheter equipped with a low invasion needle became possible also in myocardial infarction and angina pectoris, and is under clinical application as an angiogenesis therapy. For example, it has been reported that ischemia is improved for unstable angina by injecting a VEGF gene plasmid directly into heart muscle (Circulation, 98, 2800-2804 (1998)). Also, it was considered that PDGF is concerned in the angiogenesis after stroke, because its increase was observed in nerve cell of the phenanbla (the tissue is not dead by infarction but cannot perform its function) region of infarct focus of a cerebral infarction patient (Stroke, 28, 564-573 (1997)). Gene therapy and the like using a vector to the brain via cerebrospinal fluid from cerebellomedullary cistern have also been attempted on the ischemic cerebrovascular accidents. These treatments are a therapeutic angiogenesis (regeneration) therapy which prompts development of collateral circulation passage to the ischemic region and is a tissue regeneration therapy by the differentiation induction of tissue stem cells. However, clinical application of these gene therapy and cell therapy have many problems in terms of ethics, safety (immunity, infection, cancer, etc.), flexibility, economy and the like.
As a reopening therapy at the time of blood vessel obstruction in ASO, myocardial infarction, angina pectoris, arteriosclerosis and the like, PTCA (percutaneous transluminal coronary angiopathy) has been carried out with good results. However, it is known that restenosis is induced by the injury of vascular endothelial cells around the obstruction due to forced vasodilation by balloon dilation, Stent indwelling and the like. As a method for preventing restenosis, a platelet agglutination inhibitor or the like is administered, but this is still an unsatisfactory state. Recently, drugs such as antibiotics and carcinostatic agents (rapamycin, sirolimus, etc.) and a Stent coated with a radioisotope preparation such as β rays have been developed with good results on the prevention of restenosis (N. Eng. J. Med., 346(23), 1769-1771 (2002)). However, these methods also have many problems from a long-term point of view. Accordingly, concern is directed toward a medicament which enhances platelet agglutination inhibitory action at topical injured regions of vascular endothelial cells and damage repairing action by endothelial cell growth.
On the other hand, prostaglandin (PG) is a natural physiologically active substance biosynthesized from PGH2 in a metabolic pathway in the living body, which is called arachidonic acid cascade. The biosynthesis enzymes from arachidonic acid to PGH2 are called cyclooxygenase (COX), and COX-1, COX-2 and COX-3 are known at present (Proc. Natl. Acad. Sci., 99, 1371 (2002)). In addition, compounds which inhibit these enzymes are generally used as antipyretic, analgesic and anti-inflammatory agents and agents for preventing circulatory organ system diseases, as non-steroidal anti-inflammatory drug (NSAID). Particularly, COX-2 induced in inflammation regions is concerned in the biosynthesis of PGI2, PGE2 and the like. These biosynthesized PGs are concerned in the onset of pyrexia, pain and inflammation in the inflammation regions and healing thereof. That is, the PGs biosynthesized at the inflammation regions directly act as inflammation-causing agents, induce various inflammatory cytokines, evoke inflammation, and accelerate healing thereof.
On the other hand, it is known that patients who took NSAID for a prolonged period of time have significantly low mortality rate by large bowel cancer and lung cancer (N. Eng. J. Med., 328, 1313-1316 (1993)). It is said that this action has a cancer cell growth inhibitory action, because angiogenesis for cancer tissue growth is inhibited through the biosynthesis inhibition of PGI2, PGE2 and the like by NSAID. That is, an anti-angiogenesis therapy which controls growth and metastasis of tumors by inhibiting angiogenesis is drawing attention as a new strategy of cancer treatment. Also, it is known that a COX-2-selective inhibitor does not induce gastric ulcer when it is administered, but prolongs healing of gastric ulcer. There is a report stating that its cause is inhibition of angiogenesis action for repairing of injured tissues (Am. J. Med., 104, 43S-51S (1998)). In addition, selective COX-2 inhibitors control the angiogenesis accompanied by inflammation (Jpn. J. Pharmacol., 75, 105-114 (1997)).
It is known that PGI2 has a markedly strong platelet agglutination inhibitory action, as well as actions such as platelet adhesion, vasodilation and gastric acid secretion inhibition. In addition, PGE2 administration accelerates accumulation of inflammatory cells including monocyte and production of inflammatory cytokine (e.g., IL-1 (interleukin-1), IL-8, IL-6, IFN-α (interferon-α), TNFα (tumor necrosis factor α), and NO (nitric monoxide), etc.), and acts as an inflammation-causing agent.
JP-A-6-87811 discloses in its specification that the oxime derivative represented by formula (I) which is described later or a non-toxic salt thereof, to be used in the present invention as a PGI2 agonist (IP agonist), is useful for the prevention and/or treatment of thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension and the like, because it has platelet agglutination inhibition, platelet adhesion inhibition, vasodilation and gastric acid secretion inhibition actions, but it does not describe or suggest on the angiogenesis action by exerting vascular endothelial cell and vascular smooth muscle cell growth action based on the endogenous repair factor production acceleration action, and on the various cell and organ diseases (the above-described diseases to be prevented and treated (repair regeneration) by HGF) by differentiation induction of various stem cells caused by these endogenous repair factor production acceleration action and the like.
Also, it is reported in Diabetologia., 40, 1053-1061 (1997) that a PGI2 derivative Beraprost ((±)-(1R,2R,3aS,8bS)-2,3,3a,8b-terahydro-2-hydroxy-1-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butanoic acid sodium salt) increases HGF production in vascular endothelial cells in vitro and shows endothelial cell growth action, but there are no descriptions on the angiogenesis accelerating action by the topical administration of persistent preparation of Beraprost and on its usefulness for the prevention and treatment of various organ diseases.
In addition, PGE2 is known as a metabolic product in the arachidonic acid cascade, and it is known that its actions have various functions such as cell protection action, uterine contraction action, pain producing action, digestive organ peristalsis acceleration action, stimulation action, gastric acid secretion inhibition action, blood pressure reducing action, diuretic action and the like.
From the studies in recent years, it has been revealed that subtypes having respectively different roles are present in the PGE2 receptor. The subtypes known at present are roughly divided into four, and are respectively called EP1, EP2, EP3 and EP4 (J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)). By examining their share of roles and thereby finding a compound which does not bind to other subtype receptors, it became possible to obtain a medicament having less side effects.
For example, JP-A-11-193268 discloses in its specification that a compound represented by formula (I-a), a non-toxic salt thereof, or a prodrug or cyclodextrin clathrate thereof, which is used in the present invention as an EP2 agonist, is useful in preventing and/or treating immune diseases (e.g., autoimmune disease, organ transplantation, etc.), asthma, osteogenesis abnormality, nerve cell death, hepatopathy, premature delivery, abortion, retinal nerve diseases such as glaucoma, and the like, but it does not describe or suggest on the endogenous repair factor releasing action, stem cell differentiation induction action and angiogenesis acceleration action.
For example, WO00/03980 discloses in its specification that a compound represented by formula (I-b), a non-toxic salt thereof, or a cyclodextrin clathrate thereof, which is used in the present invention as an EP4 agonist, is useful in preventing and/or treating diseases including immune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren syndrome, rheumatoid arthritis, autoimmune diseases such as systemic lupus erythematosus, rejection after organ transplantation, etc.), asthma, osteogenesis abnormality, nerve cell death, lung disease, hepatopathy, acute hepatitis, glomerulonephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory reaction syndrome, burn pain, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still disease, Kawasaki disease, burn injury, systemic granuloma, neoplastic colitis, Crohn disease, hypercytokinemia at the time of dialysis, multiple organ failure, shock, sleep abnormality, platelet agglutination and the like, but it does not describe or suggest on the endogenous repair factor releasing action, stem cell differentiation induction action and angiogenesis acceleration action.